Most Read Articles
Jairia Dela Cruz, Yesterday
The selective serotonin reuptake inhibitor escitalopram holds promise in the prevention of Alzheimer’s disease, reducing amyloid-β-42 levels in cerebrospinal fluid and brain tissue in older adults with normal cognitive function, according to recent evidence.
25 Nov 2020
Vitamin D deficiency may be a contributing factor to the mortality rate among patients with the novel coronavirus disease (COVID-19), reports a new study.
Pearl Toh, 6 days ago
Inhaled corticosteroid (ICS) should be the mainstay of long-term asthma management — such is the key message of the latest Singapore ACE* Clinical Guidance (ACG) for asthma, released in October 2020.
Elvira Manzano, 17 Nov 2020
Invasive fungal infections, particularly those caused by Candida species, are common in hospitalized, immunocompromised, or critically ill patients and are associated with considerable morbidity and mortality.

Role of edoxaban in AF management in elderly and Asian patients

Prof. Hung-Fat Tse
Chair of Cardiovascular Medicine
Chief of Cardiology Division
University of Hong Kong
04 Sep 2020

Non-vitamin K antagonist oral anticoagulants (NOACs) are a valid option for stroke prevention in patients with atrial fibrillation (AF) due to their comparable efficacy and reduced risk of major bleeding vs warfarin. At the 28th Annual Scientific Congress of the Hong Kong College of Cardiology, Professor Hung-Fat Tse of the Queen Mary Hospital in Hong Kong discussed the advantages of edoxaban (Lixiana®, Daiichi Sankyo) in stroke prevention specifically in high-risk elderly patients with AF.

AF burden in the ageing Asian population

“Despite the relatively low prevalence of AF in Asia [ie, approximately 1 percent] vs other regions, we have a higher overall AF burden because of our proportionally older population,” said Tse. [Heart Rhythm 2013;10:1082-1088]

“This increasing AF burden in the elderly Asian population is mainly driven by the increased risk of AF-related stroke and transient ischaemic attacks,” Tse continued. [J Neurol Neurosurg Psychiatry 2017;88:744-748] Furthermore, Asian patients are at higher risk of haemorrhage vs Caucasian population. [Lancet Neurol 2010;9:167-176]

Emergence of NOACs

“The vitamin K antagonist warfarin, traditionally used to reduce the risk of stroke and thromboembolism in high-risk patients with nonvalvular AF, is associated with an increased risk of intracranial haemorrhage [ICH] that is more pronounced in Asian patients,” noted Tse. [Heart Rhythm 2013;10:1082-1088; Am Coll Cardiol 2007;50:309-315]

Aside from their efficacy noninferiority demonstrated in randomized controlled trials, the NOACs dabigatran, apixaban, rivaroxaban and edoxaban are associated with significantly lower incidences of major haemorrhage vs warfarin. [Nat Rev Cardiol 2014;11:290-303; N Engl J Med 2013;369:2093-2104] “All NOACs share a feature of preserved efficacy with improved safety vs warfarin in Asian patients with AF,” commented Tse. [J Formos Med Assoc 2017;116:591-598]

Edoxaban evidence: ENGAGE AF–TIMI 48

The randomized, double-blind ENGAGE AF–TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) trial previously demonstrated that both high-dose (60/30 mg QD) and low-dose (30/15 mg QD) regimens of edoxaban were noninferior to warfarin in reducing stroke or SEEs, with significantly lower rates of bleeding and death from cardiovascular (CV) causes. [N Engl J Med 2013;369:2093-2104]

Edoxaban in the elderly

“ENGAGE AF–TIMI 48 included a large number of elderly patients. After stratifying according to age [<65 years (n=5,497), 65–74 years (n=7,134) and ≥75 years (n=8,474)], edoxaban’s benefit vs warfarin in reducing haemorrhagic stroke, ICH and fatal bleeding events was more dramatic in the elderly [≥75 years] population,” noted Tse. [J Am Heart Assoc 2016;5:e003432]

Edoxaban in Asian patients

“Approximately 48 percent of East Asian patients who generally had lower body weight and poorer renal function required a dose reduction in the subanalysis of ENGAGEAF–TIMI 48 trial,” said Tse. Both patients on full and reduced dose of edoxaban had a lower annualized rate of stroke/SEEs vs those on warfarin (1.34 percent for edoxaban 60/30 mg QD and 2.52 percent for edoxaban 30/15 mg QD vs 2.62 percent for warfarin) (edoxaban 60/30 mg QD vs warfarin: hazard ratio [HR], 0.53; p=0.02) (edoxaban 30/15 mg QD vs warfarin: HR, 0.98; p=0.93). [Circ J 2016;80:860-869]

“Major bleeding was also significantly reduced with both edoxaban dosing regimens vs warfarin,” Tse added. [Circ J 2016;80:860-869]

Efficacy and safety at reduced dose

Off-label dose adjustments of NOACs may have important efficacy and safety implications. The ORBIT–AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase II) registry showed that a significant minority (almost 1 in 8) of patients received dabigatran, rivaroxaban and apixaban doses that were not consistent with prescribing information, and that NOAC over- and underdosing were associated with an increased risk of adverse events. [J Am Coll Cardiol 2016;68:2597-2604] (Table 1)

DAI-137md01

A subanalysis of ENGAGE AF–TIMI 48 assessed whether a 50 percent dose reduction of edoxaban (higher dose, 60 mg/day reduced to 30 mg/day; lower dose, 30 mg/day reduced to 15 mg/day) in patients with creatinine clearance of 30–50 mL/min, body weight ≤60 kg, or receiving concomitant medication with potent P-glycoprotein interaction would prevent excess drug concentrations and reduce the risk of bleeding events. [Lancet 2015;385:2288-2295]

A total of 5,356 patients (25.4 percent) received the reduced dose of edoxaban at randomization. While a trend towards a higher rate of ischaemic and bleeding events was observed in those who received a reduced dose (including patients on warfarin who had a placebo dose reduction), edoxaban dose reduction was associated with improved safety (major bleeding: higher dose, pinteraction=0.02; lower dose, pinteraction=0.002) and the efficacy of edoxaban vs warfarin was preserved (stroke or SSEs: higher dose [60/30 mg QD], pinteraction=0.85; lower dose [30/15 mg QD], pinteraction=0.99). [Lancet 2015;385:2288-2295]

“These results highlight that tailoring edoxaban dose on the basis of clinical factors alone helps achieve the dual goal of preventing excess drug concentration and optimizing individual patients’ risk of ischaemic and bleeding events,” explained Tse.

Pharmacokinetic drug interactions

Concurrent use of NOACs with certain drugs, such as amiodarone, fluconazole, rifampin and phenytoin, may be associated with an increased risk of major bleeding compared with using a NOAC alone. [JAMA 2017;318:1250-1259]

“There is extensive information regarding edoxaban’s drug interactions with various drugs, making it easier to use in various scenarios via dose adjustment recommendations,” noted Tse. [Eur Heart J 2018;39:1330-1393]

In light of the coronavirus disease 2019 (COVID-19) pandemic, the European Society of Cardiology has also released a guidance document with recommendations based on recent experience and observed interactions of NOACs with currently used COVID-19 therapies. [https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance]

Summary

Stroke prevention in patients with AF is of increasing importance, especially among the elderly Asian population. NOACs such as edoxaban may provide greater benefit than warfarin in the elderly and Asian patients with AF in terms of stroke prevention, as demonstrated in ENGAGE AF–TIMI 48. In addition, in view of the available reduced-dose data for edoxaban, it represents a viable treatment option in this high-risk population.

 

Related MIMS Drugs

Digital Edition
Asia's trusted medical magazine for healthcare professionals. Get your MIMS Doctor - Hong Kong digital copy today!
Sign In To Download
Editor's Recommendations
Most Read Articles
Jairia Dela Cruz, Yesterday
The selective serotonin reuptake inhibitor escitalopram holds promise in the prevention of Alzheimer’s disease, reducing amyloid-β-42 levels in cerebrospinal fluid and brain tissue in older adults with normal cognitive function, according to recent evidence.
25 Nov 2020
Vitamin D deficiency may be a contributing factor to the mortality rate among patients with the novel coronavirus disease (COVID-19), reports a new study.
Pearl Toh, 6 days ago
Inhaled corticosteroid (ICS) should be the mainstay of long-term asthma management — such is the key message of the latest Singapore ACE* Clinical Guidance (ACG) for asthma, released in October 2020.
Elvira Manzano, 17 Nov 2020
Invasive fungal infections, particularly those caused by Candida species, are common in hospitalized, immunocompromised, or critically ill patients and are associated with considerable morbidity and mortality.